Reviews of Reproduction (1996) 1, 144–148
© 1996 Journals of Reproduction and Fertility
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Although menchymal induction of epithelial growth and dif-ferentiation is well recognized in embryogenesis, the same principle has rarely been considered in studies on placental development. However, careful examination of placental mem-brane dev elopment across species shows a strong correlation between trophoblast (epithelial) growth and differentiation on the one hand, and the migration and dev elopment of men-chymal tissues that make intimate contact with that tropho-blast, on the other.
The basic principles of placental development in mammals,and the ev idence for menchymal stimulation of trophoblast growth during the process, are summarized (Fig. 1). The first differentiation event in mammalian development occurs at, or just before, the blastocyst stage of embryonic growth and in-volves the differentiation of the outermost layer of cells into an epithelial phenotype, the trophoblast (e 1 in Fig. 1). The re-maining cells form the inner cell mass (ICM) which eventually becomes the embryo, whereas the trophoblast, along with ICM-deriv ed mesodermal and endodermal
components, forms the placenta. Next, extra-embryonic endoderm differentiates and migrates from the ICM (e 2 in Fig. 1) to form the yolk sac; the combined endoderm and trophoblast layers are referred to as chorion. Mesoderm then migrates between the endoderm and trophoblast layers to form the tri-layered, vascularized yolk sac placental membrane (e 3 in Fig. 1) and the chorion envelops the embryo to form the amnion (e 4 and 5 in Fig. 1). This is the limit of placental dev elopment in most marsupials but in eutherian mammals there is considerable further development,involving formation of the chorioallantois. This aris through migration of allantoic mesoderm from the hind gut area of the
embryo (e 4 in Fig. 1) and its subquent fusion with the chorion (e 5 in Fig. 1). In many species, an endoderm layer migrates along with the mesoderm to give ri to an allantoic sac (as shown in Fig. 1), but in others, such as primates, the endoderm forms a rudimentary duct and there is no fluid filled sac. The blood vesls that form within the menchyme of the chorioallantois constitute the fetal vasculature of the placenta,the major arteries and veins of which leave and enter the fetus via the umbilicus.
Throughout the development of the placenta, the epithelial trophoblast remains as the outermost layer and it is this tissue that makes an ev er increasing area of intimate contact with maternal tissue
s. To acheiv e this, it undergoes considerable proliferation and differentiation and it develops a bewildering array of phenotypes, including the ability to inv ade maternal tissues, while at the same time avoiding maternal immunologi-cal recognition and rejection. Trophoblast growth and differen-tiation occur at different rates and in many different ways among mammals and their interaction with the maternal endo-metrium has been shown to have a profound effect (Wooding and Flint 1994). However, there is also an obvious fetal drive to placental membrane dev elopment and it is possible to relate each significant stage of trophoblast proliferation and differen-tiation to the migration of extra-embryonic endoderm and/or mesoderm in contact with that trophoblast. For example, the rapid growth and expansion of the trophoblast layer in most artiodactyla, especially the porcine and ruminant species, can be related to endoderm migration. Likewi, early or ‘primary’syncytiotrophoblast formation in rodents and humans is allied to early endoderm and/or mesoderm migration (Gardner
我会一直想你Roles of menchymal–epithelial interactions and hepatocyte growth
factor-scatter factor (HGF-SF) in placental development
Francesca Stewart
TBA Equine Fertility Unit, Department of Clinical Veterinary Medicine, University of Cambridge and
下面痒用什么药The Babraham Institute, Babraham, Cambridge CB2 4AT, UK
The major components of the mammalian placental membranes are an epithelial surface layer,the trophoblast, and a heav ily v ascularized menchyme, the allantoic menchyme. The trophoblast layer makes the most intimate contact with maternal tissues and it displays a wide range of unusual, often inv asiv e, phenotypes. Howev er, one common feature of trophoblast development in all species is a strong correlation between the proliferation and differentiation of this epithelial layer and its physical contact with dev eloping allantoic menchyme. This suggests an epithelial–menchymal interaction inv olv ing paracrine signals from allantoic menchyme acting on adjacent trophoblast. The expression patterns of veral growth factors and their receptors, including hepatocyte growth factor-scatter factor (HGF-SF) and its recep-tor, c-met, support the hypothesis. Furthermore, HGF-SF and c-met gene knockout studies in mice indicate that HGF-SF and c-met are both esntial for placental development. HGF-SF, in addition to being a potent mitogen, caus scattering and morphogenic changes in cultured cells and is believed to be an important mediator of the induction of epithelial differentiation during embryogenesis. This rev iew ev aluates the importance of menchymal induction of trophoblast growth and differentiation in placental dev elop
ment and argues that HGF-SF is a crucial component of the menchymal stimulus.
HGF-SF and placental development 145
1983). Howev er, the most dramatic changes in growth and phenotype occur after allantoic menchyme makes contact with trophoblast to form the chorioallantois. This initiates proliferation and migration of labyrinthine trophoblast in the murine placenta, chorionic villi formation in the haemochorial placenta of primates and the formation of noninv asiv e chori-onic v illi within the epitheliochorial placenta of the pig and hor. Growth factors and cytokines are the most likely mediators of the allantoic menchymal stimulus to trophoblast and this rapidly growing, heavily vascularized tissue is a rich source of such factors. For example, expression of insulin-like growth factor II (IGF-II) is extremely high in allantoic menchyme (Redline et al ., 1993; Lennard et al ., 1995) and the reduced size of IGF-II knockout mice has been partly attributed to reduced placental size (DeChiara et al.
, 1991). The mitogenic action of
Fig. 1.A general scheme for the development of the mammalian placenta (bad on Mossman, 1987). 1. The outermost cells of the blastocyst differentiate to form trophoblast (blue), while the remainder form the inner cell mass (ICM) which becomes the embryo. 2. Extra-embryonic endoderm (red) migrates and, together with trophoblast, forms the chorion. 3. Extra-embryonic mesoderm (orange) migrates between the trophoblast and endoderm to form the tri-layered yolk sac placenta; t
his is the limit of placental development in most marsupials but is only temporary in eutherians. 4. The chorion expands around the embryo to form the amnion (complete in 5) and the allantois (endoderm, red;mesoderm, pink) migrates from the embryo. 5. Allantoic mesoderm fus with chorion to form the chorioallantois. This forms the definitive placenta in all eutherian mammals and it inv olv es considerable proliferation and differentiation of trophoblast (blue). Not all eutherian placentae have an allantoic cavity as shown here, but they all posss allantoic menchyme, the vesls of which form the fetal vasculature of the placenta. This menchymal tissue is always in contact with the trophoblast that makes the most intimate contact with maternal tissues. It is this trophoblast that proliferates and invades to the greatest extent and shows the widest range of phenotypes. However, it does not undergo the changes until allantoic mesoderm makes contact with it.
IGF-II in the fetus appears to be mediated v ia its interaction with the IGF-I (type 1) receptor, rather than the IGF-II receptor, although the placenta may posss a third, as yet unidentified receptor (Baker et al., 1993). The expression of colony-stimulating factor 1 (CSF-1) is also high in allantoic menchyme (stroma) of the chorionic villi within the human placenta and its recep-tor, c-fms, is expresd in the trophoblast layer (Kanzaki et al., 1992). Likewi, keratinocyte growth factor and its
receptor show the same pattern of expression in the chorionic v illi of rhesus monkeys (Izumi et al., 1996). Howev er, ev idence is emerging that possibly the most important growth factor in terms of trophoblast growth within the chorioallantoic placenta is hepatocyte growth factor-scatter factor (HGF-SF).
Hepatocyte growth factor-scatter factor (HGF-SF) HGF-SF was first described and partially characterized in 1984 as hepatocyte growth factor (HGF), owing to its ability to stimu-late the proliferation of hepatocytes in vitro(Nakamura et al., 1984) and later, as scatter factor (SF) through its ability to make epithelial cells scatter in vitro(Stoker et al., 1987). Sev en years later, human HGF and SF were shown to be identical (Weidner et al., 1991), hence the rather cumbersome name of hepatocyte growth factor-scatter factor. HGF-SF has now been shown to exert many additional actions on cells, including induction of morphogenesis, the stimulation of T-cell adhesion to endo-thelium and enhancement of neurone survival (Brinkmann et al., 1995; Zarnegar and Michalopoulos, 1995). It has been postulated to play a crucial role in tissue regeneration following injury and this has stimulated a great deal of interest in the molecule and its mode of action.
HGF-SF is a heparin-binding protein that is creted as a large, single-chain, inert precursor (pro-HGF-SF). It then under-goes proteolytic digestion to give ri to the active dimer, which consists of a
60 000 kDa α-subunit and a 30 000 kDa β-subunit, linked by a single disulfide bond. It is structurally related to plasminogen and other rine proteas but lacks enzyme activity due to veral amino acid substitutions within the cat-alytic site of the rine-protea-like domain. The receptor for HGF-SF is the product of the proto-oncogene, c-met, and cells co-transfected with the growth factor and its receptor cau tumours in nude mice (Tsarfaty et al., 1994). The intracellular domain of the β-subunit of the receptor has tyrosine kina activity and transduces all the effects of HGF-SF. Menchymal expression of HGF-SF
怎样共享打印机到另一台电脑
In nearly all tissues examined, both during development and in the adult, HGF-SF is expresd by menchymal tissues and c-met is expresd by adjacent epithelia. For example, in the liver, HGF-SF is expresd by nonparenchymal cells and c-met by hepatocytes (Hu et al., 1993) and in the dev eloping mam-mary gland, fibroblasts express HGF-SF, whereas the luminal and myoepithelial cells express c-met(Niranjan et al., 1995). Expression of HGF-SF by menchyme is also supported by the finding that both the mou and human HGF-SF promoter quences are activ e in menchymal, but not epithelial, cells (Plaschke-Schlutter et al., 1995). Furthermore, expression pat-terns of HGF-SF and c-met in the mou embryo (Sonnenberg et al., 1993) suggest a fundamental role in dev elopment. For example, in all the major organs, including the stomach, lung, v ertebra an
d intestine, HGF-SF was expresd in the men-chyme and c-met was expresd in the adjacent epithelium. This relationship provides evidence for a role for HGF-SF in the dev elopmental induction of epithelial cell differentiation by menchyme and it is supported by experimental ev idence in the developing kidney (Woolf et al., 1995) and rabbit limb bud (Takebayashi et al., 1995) and in the gene knockout studies de-scribed below.
Gene knockout experiments
Two parate gene targeting studies, aimed at eliminating HGF-SF expression in mice, were reported early in 1995 (Schmidt et al., 1995; Uehara et al., 1995) and in both, all of the homozygous mutant embryos died before birth. About 10% of the homozygous embryos were dead at day 13 of gestation and all were dead by days 17–18, demonstrating a fundamental role for HGF-SF in development. However, while Uehara et al. (1995) reported major placental failure, but no developmental abnor-malities in their HGF-SF null embryos, Schmidt et al. (1995) showed evidence of liver deficiency in their embryos in addition to the placental defect. The discrepancy between the two studies was attributed to the stage at which the embryos were analyd; Uehara et al. (1995) analyd embryos at day 13.5, whereas Schmidt et al. (1995) examined embryos at day 14.5. However, the placental failure in both experiments was identical and appeared to be due to a comple
te lack of dev elopment of labyrinthine trophoblast. This type of trophoblast does not de-v elop in rodents until allantoic menchyme makes contact with trophoblast to form the chorioallantois, and it is therefore a prime example of the menchymal stimulation of tropho-blast growth and differentiation outlined above. Since HGF-SF is produced by menchyme, the abnce of labyrinthine trophoblast in both studies was almost certainly caud by the lack of HGF-SF in the allantoic menchyme (e Fig. 2, which shows a mou conceptus at day 10.5 of gestation with its developing placenta and the area in which labyrinthine tropho-blast would normally develop).
Uehara et al. (1995) also showed that normal (wild-type) mou allantoic menchyme produced HGF-SF activity when cultured in vitro and that mou trophoblast cells cultured in vitro in rum-free medium responded to added recombinant-deriv ed human HGF-SF. The experiments clearly support the hypothesis that allantoic menchyme-deriv ed HGF-SF stimulates trophoblast growth and dev elopment within the chorioallantoic placenta of the mou. The conclusion is that the allantoic menchyme makes contact with the trophoblast and induces proliferation, differentiation or both process via c-met.
语文学习与评价The c-met gene was also interrupted in mice using hom-ologous recombination and the resulting homozygous mutants were identical to the HGF-SF null mice (Bladt et al. 1995). That is, the embryo
s died at the same stage of gestation, showed the same placental and liv er defects and also exhibited a lack of specific skeletal muscle development, which was confirmed by re-examination of the HGF-SF knockout embryos. Thus, unlike many other ubiquitous growth factors and their receptors, HGF-SF and c-met appear to be esntial for embryonic and placental development, at least in mice.
146 F. Stewart
Placental expression of HGF-SF
Although the cDNA quence for human HGF-SF was obtained originally from a placental cDNA library (Nakamura et al., 1989), and was purified from human and rodent placental tissues (Hernandez et al., 1992; Jin et al., 1993), there have been v ery few studies localizing sites of expression of HGF-SF in mammalian placentae. The first immunohistochemical study suggested that HGF-SF was prent in the syncytiotrophoblast layer lining the chorionic villi of the human placenta (Wolf et al., 1991). This was unexpected as it suggested epithelial expression of the growth factor. Howev er, a more recent study of the human placenta, using both in situ hybridization and immuno-histochemistry, showed HGF-SF expression in the allantoic menchyme (stroma) of the ch
orionic villi and its receptor in trophoblast, as might be expected (Saito et al., 1995). The authors also showed that HGF-SF stimulated DNA synthesis in human cytotrophoblast cells cultured in rum-free medium.
The author’s own study on the hor placenta also dem-onstrated HGF-SF in menchyme and c-met in trophoblast (Stewart et al., 1995). The equine placenta is unusual in that the trophoblast cells of only a discrete annulate region of the placenta, the chorionic girdle, become binucleate and invasive, while the remaining trophoblast remains noninvasive (Allen and Moor, 1972). The chorionic girdle develops through rapid mul-tiplication of trophoblast cells overlying the point of abutment of the enlarging allantois and regressing yolk sac, and the most likely explanation for this localized area of trophoblast differ-entiation is a mitogenic stimulus from allantoic menchyme acting on trophoblast that is adjacent to, but not part of, the chorioallantoic membrane. All of the trophoblast in contact with allantoic menchyme responds to the stimulus, but only that area of trophoblast that becomes the chorionic girdle acquires an invasive phenotype becau the chorion in this region is not fud to the allantois and therefore has a different phenotype and responds in a different way. Furthermore, in situ hybrid-ization demonstrated mRNA encoding HGF-SF in allantoic mes-enchyme and mRNA encoding c-met in the trophoblast, but with particularly high concentrations in the chorioni
c girdle (Stewart et al., 1995). In addition, both recombinant-derived human and mou HGF-SF are mitogenic to hor cytotrophoblast cells grown in rum-free medium (F. Stewart and E. Gherardi, un-published). The results indicate an important role for HGF-SF in dev elopment of the hor placenta and prov ide a feasible explanation of chorionic girdle development.
Although in situ hybridization studies have not been carried out on mou placental tissues, Uehara et al.(1995) have dem-onstrated that HGF-SF was produced by cultured mou allan-toic menchyme and that explants of mou trophoblast proliferated in respon to HGF-SF. It is therefore almost cer-tain that, as with human and hor placental membranes, mou allantoic menchyme express HGF-SF and the trophoblast layer express c-met. Thus, when the two tissues make intimate contact in mice, the HGF-SF stimulates prolifer-ation, differentiation, or both process, of the cytotrophoblast into a highly specialized labyrinthine trophoblast that is necess-ary for full placental development.
Conclusions
Menchymal–epithelial interactions are important in placental dev elopment, particularly during formation of the chorio-allantoic placenta in all eutherian mammals. Allantoic men-chyme is a rich
和风习习source of growth factors and cytokines, and the appear to act in a paracrine fashion on adjacent tropho-blast to induce proliferation and differentiation. Ev idence is accumulating to suggest that HGF-SF is one of the crucial growth factors involved in this process.
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